Esters and salts of gamma-(3-indoyl)-gamma-ketopropylphosphonic acids



United States Patent ESTERS AND SALTS 0F 'y-(3-INDOYL)-'y-KETO-PROPYLPHOSPHONIC ACIDS Jacob Szmuszkovicz, Portage Township, KalamazooCounty, Mich., assignor to The Upjohn Company, Kalamazoo, Mich., acorporation of Michigan No Drawing. Application June 27, 1957 Serial No.668,307 1 11 Claims. (Cl. 260 319) The present invention relates tonovel organic compounds and is more particularly concerned with monoanddialkyl esters of 'y-(3-indolyl)-' -keto-propylphosphonic acids, and thealkali-metal salts of the mono esters of'y-(3-indolyl)-'y-keto-propylphosphonic acids.

The novel dialkyl esters of 'y-(3-indolyl)-'y-keto-propylphosphonicacids possess valuable pharmacological activity. These compounds havesedative and analgetic I activity. In addition, the dialkyl esters haveshown herbicidal properties.

The dialkyl esters are also valuable intermediates in the preparation ofthe pharmacologically active monoalkyl esters of 'y-(3-indolyl)y-keto-propylphosphonic acids and the alkali-metal salts thereof. Thenovel mono-' alkyl esters and alkali-metal salts have shown analgeticactivity.

The novel compounds of this invention can be represented by thefollowing general formula:

ii Ii/ CCHaCHzP I verted to the desired hydroxy radical byhydrogenolysis in the presence of a catalyst, advantageously palladiumon charcoal, employing the general procedure more fully disclosed in U.S. Patent 2,708,197. Benzyloxy radicals which are so employed includebenzyloxy, benzhydryloxy, halobenzyloxy, e. g., para-chlorobenzyloxy andpara,para'- dichlorobenzhydryloxy, alkylbenzyloxy, e. g.,para-methylbenzyloxy and para,para' dimethylbenzhydryloxy,alkoxybenzyloxy, e. g., para-methoxybenzyloxy and para,para'-dimethoxybenzhydryloxy, and the like. R; represents a primary orsecondary lower-alkyl radical containing from one to four carbon atoms,inclusive, such as methyl, ethyl, propyl, butyl, isopropyl, andisobutyl. R represents hydrogen, a primary or secondary loweralkylradical containing from one to four carbon atoms,

2,877,234 Patented Mar- 1Q, 1

ice

or secondary trialkyl phosphite to produce a dialkyl ester of a'y-(3-indolyl)-'y-keto-propylphosphonic acid, employing the generalprocedure described by Myers et al., J. Amer. Chem. Soc. 77, 3101, 1955.

The monoalkyl esters of 'y-(3-indolyl)--y-keto-propylphosphonic acidsare prepared by subjecting the dialkyl esters to alkaline hydrolysisutilizing, e. g., sodium hydroxide, potassium hydroxide, sodiumcarbonate, and the like. The hydrolysis is advantageously conducted at atemperature between about eighty and about 100 degrees centigrade for aperiod of between about two to about ten hours, preferably about eighthours at about 95 degrees centigrade. It is pointed out that when R andR as shown in the above structural formula, are hydrogen and the alkylradicals R and R are derived from a: primary trialkyl phosphite, thenthe alkaline hydrolysis ordinarily results in a mixture of products,viz., the monoalkyl ester of a'y-[3-(l-alkyl)-indolyl]-'y-keto-propylphosphonic acid'and the monoalkylester of 'y-(3-indolyl)- -keto-propylphosphonic acid. This is by virtueof the migration of one of the primary alkyl radicals to the 1- positionof the indole nucleus, the extent of such migration depending upon theparticular primary alkyl radical.

The migration does not occur when R and R are derived from secondarytrialkyl phosphites such as triisopropyl phosphite. If desired, themixture of compounds can be separated into the individual componentsaccording to conventional procedure.

However, such mixtures can be avoided and the compounds producedseparately, if so desired. For example, the monoalkyl esters of-(3-indolyl)-'y-keto-propylphosphonic acid (i. e., R and R are hydrogen)are prepared by reacting an alcoholic solution of 'y-(3-indolyl)--keto-propylphosphonic acid at room temperature (about twenty to thirtydegrees centigrade) with an ethereal solution containing an equimolaramount of a diazoalkane having from one to four carbon atoms, inclusive,e. g., reacting one mole of 'y-(3-ll1d0lyU-7-kfl0- propylphosphonic acidwith one mole of diazopropane results in the preparation of one mole ofthe monopropyl ester of y-(3-indolyl)--y-keto-propylphosphonic acid. The*y-(3-indolyl)-'y-keto-propylphosphonic acid can be prepared from itsmonoisopropyl ester by heating the monoisopropyl ester in the presenceof hydrogen'ion and a polar solvent such as water, acetic acid, and thelike.

The monoalkyl esters of -[3-(-l-alkyl)-indolyll-'y-ketopropylphosphonicacids are produced separately by reacting a Z-sec-aminoethyl3-(l-alkyl)-indolyl ketone quaternary ammonium or acid addition saltwith a primary or secondary trialkyl phosphite to produce a dialkylester of a 'y- 3- l-alkyl -indolyl --,'-keto-propylphosphonic acid,followed by alkaline hydrolysis of the dialkyl ester.

The preparation of mixed dialkyl esters can be carried out by reacting adiazoalkane as exemplified herein and a monoalkyl ester of a'y-(3-indolyl)-'y-keto-propylphosphonic acid. For example, propyl butyl'y(3-ind0lyl)-'yketo-propylphosphonate can be prepared by reactingpropyl 'y-(3-indolyl)-'y-keto-propylphosphonate with an inclusive, suchas methyl, ethyl, propyl, butyl, isopropyl,

quaternary ammonium or acid addition salt with a primary equimolaramount of diazobutane to prepare the mixed diester, namely, propyl butyl-(3-indolyl)-'y-keto-propylphosphonate. I

The alkali-metal salts of the monoalkyl esters of 7 -0- indolyl)--keto-propylphosphonic acids are prepared by reacting a monoalkyl esterwith a stoichiometric amount of alkali-metal (including ammonium)hydroxide or carbonate such as ammonium hydroxide, sodium hydroxide,potassium hydroxide, sodium carbonate, sodium bicarbonate, potassiumcarbonate, and the like.

The primary and secondary trialkyl phosphites which are employed asstarting reactants in the present invention are prepared in knownmanner, e. g., as disclosed in Organic Reactions, vol. VI, page 286,1951-10111: Wiley and Sons, Inc. Representative trialkyl phosphitesinclude trimethyl phosphite, triethyl phosphite, tripropyl phosphite,tributyl phosphite, triisobutyl phosphite, triiso- .propyl phosphite,tri-(sec-butyl) phosphite, and the like.

The diazoalkanes employed in the present invention can be preparedaccording to the procedure disclosed in J. Org. Chem. 21, 1017, 1956.Representative diazolkanes which can be employed include diazomethane,dia- .zoethane, diazopropane, diazobutane, and the like.

The starting 2-sec-aminoethyl 3-indolyl ketone quaternary ammonium andacid addition salts can be prepared by reacting a 3-indolyl methylketone with formaldehyde and a dialkylamine or heterocyclic secondaryamine ,in the presence of an inert solvent. The reaction is generallycarried out under acid conditions, i. e., a pH of less than seven. Inertsolvents can include methanol, ethanol, and isoamyl alcohol althoughwhen aqueous formaldehyde is employed no solvent is necessary.Representative amines which can be employed include dimethylamine,diethylamine, diisopropylamine, pyrrolidine, piperidine, morpholine, andthe like. The acid conditions generally necessary for completion of thereaction can be brought about by employing the amine as an acid additionsalt such as the hydrochloride, sulfate, hydrobromide, and the like. orthe acid conditions can be brought about by the addition of an acid suchas acetic. hydrochloric, and the like, to the reaction mixture. Thereaction is carried out at a temperature between about fifty and about100 degrees centigrade and advantageously at a temperature between about65 and about 85 de rees centigrade. The thus-produced Z-sec-aminoethyl3-indolyl ketone acid addition salt can be recovered by conventionalprocedure, such as by fi tration after cooling the reaction mi ture. The.Z-sec-aminoethyl 3-indolv1 ketone free base can be produced from theacid addition salt and then converted to the quaternary ammonium salt.The free base can be roduced by di s lving t e acid addition salt inwater, adding excess alkali-metal hydroxide to the aqueous mixture.extracting the mixture with ether. washing the ether extracts withWater, drving the washed product, and evaporating to dryness. Thequaternary ammonium salts can be prepared by reacting the free base inan inert solvent with a suitable quaternarv ammonium sa t-form ngompound such as methyl iodide. ethyl bromide, butyl iodide, benzyl choride. and the like.

The 3-indolyl methyl ketones employed in the preparation ofZ-sec-aminoethyl B-indolyl ketones can be pre ared from 3-unsubstitutedindoles bv the processes outlined in'Heterocyclic Compounds, Elderfield.vol. 3, pa e 44,

- .1952Iohn Wiley and Sons, inc. The 5-benzvloxy-3-un- .substitutedindoles can be prepared according to the procedure disclosed by Burtonet al., J. Chem. Soc. 1726. 1937. Representative 5-benzyloxyindolesinclude the following: S-benzyloxyindole, S-benzhydryloxyindole, 5-(para-chlorobenzyloxy) indole, 5(para,para'-dichlorobenzhydryloxy)-indole, 5(para-methoxybenzyloxy)-indole,5-(para,para'-dimethoxybenzhydryloxy)-indole, 5-(para-ethylbenzyloxy)-indole, 5-(para,para-diethylbenzhydryloxy)-indole,and the like. A l-alkyl substituent can be attached by alkylation of al-unsubstituted 3-indolyl methyl ketone by using the procedure disclosedby Baker et al., J. Chem. Soc. 958, 1940, which involves the reac- "tionof a l-unsubstituted indole with an alkyl halide, e. g.,

methyl iodide, ethyl iodide, isobutyl bromide, hexyl iodide, andthelike, in the presence of an alkali-metal alkoxide, or by usingtheprocedure disclosed by Chemical Abstracts 49, 1006d (1955) whichinvolves the reaction :of ;& L1- ;unsub.stitute.d indole with adialkylsulfate in thepresenee of an alkali-metal hydroxide.

'The following examples are illustrative of the process and products ofthe present invention, but are not-to be construed as'limiting.

4 EXAMPLE 1 Diethyl ester of-[3-(1-e1hyl)-indolyl]--y-keto-propylphosphonic acid A.Z-DIMETHYLAMINOETHYL 3-(1-ETHYLINDOLYL) KETONE METHIODIDE A mixture of49.32 grams of 1-ethyl-3-acetylindole [C. A. 49, 1006d (1955)], 25.8grams of dimethylamine hydrochloride, and 15.85 grams ofpara-formaldehyde in 400 milliliters of absolute ethanol was refluxedfor nineteen hours. The resulting solution was evaporated to dryness onthe steam bath under vacuum. The residue was dissolved in 350milliliters of water and the solution was extracted twice with ether.

The brown aqueous solution was made basic with a solution of 33.6 gramsof potassium hydroxide in milliliters of water, with ice-bath cooling.The resulting mixture was extracted three times with ether. The combinedether extracts were washed with saturated aqueous sodium chloridesolution, dried with anhydrous sodium sulfate, and evaporated to give 56grams (87 percent yield) of Z-dirnethylaminoethyl 3-(1-ethylindolyl)ketone as an oil.

Fifteen grams of the Z-dimethylaminoethyl 3-(1-ethylindolyl) ketone wasdissolved in 65 milliliters of methanol. The solution was cooled with anice bath and then 17.5 grams of methyl iodide was added with swirlingduring a ten minute period. The mixture was kept at zero degreesCentigrade for one-half hour and then at 25 degrees centigrade for fortyminutes. The resulting crystals were filtered, washed with methanol andthen with ether, to produce Z-dimethylaminoethyl 3-(1-ethylindolyl)ketone methiodide which melted at 192 to 194 degrees centigrade,Recrystallization from methanol aiforded pale yellow needles, meltingpoint 192-194 degrees Centigrade.

B. DIETHYL ESTER OF 'y [3-(1-ETHYL)-INDOLYL]-'y- KETO-PROPYLPHOSPHONICACID A mixture of 11.2 grams of Z-dimethylaminoethyl 3-(1- ethylindolyl)ketone methiodide and fifty grams of triethyl phosphite was refluxed fortwo hours; the bath temperature was to 200 degrees centigrade. Somesolid material collected in the mouth of the condenser but most of itwas present in suspension. The suspension was cooled, diluted with 100milliliters of benzene and allowed to stand for about ten hours. Thesuspension was filtered in order to remove the solid material(trimethylethylammonium iodide). The filtrate was washed once with coldwater and twice with saturated aqueous sodium chloride solution. Thewashed solution after being dried with anhydrous sodium sulfate wasevaporated on the steam bath Monoethyl ester of 'y- [3-(1-elhyl -irz; z'olyl]-'y-ke;0 propylphosphonic acid A mixture of 0.8-gram of the -oilydiethyl ester of y-[3- I-ethyD-indolyl]--y-keto-propylphosphonic acidand a solution of 2.64 grams of potassium hydroxide in 7.92 millilitersof water was refluxed with stirringfor-seven hours. The resultingsolution was 16001.6(1 with an ice bath ,and

acidified with 4.6 milliliters oft-concentrated hydrochloric acid. Theresulting yellow oil was extracted three times with chloroform.The-combined chloroform extracts were .washed successively with waterand saturated aqueous 7 ;.-sodiux n. chloridesolution and thentdriedwithanhydrous aav'aase magnesium sulfate. The driedchloroform solutionwas evaporated to dryness at about 25 degrees centigrade and reducedpressure. There was thus obtained 0.673 gram of crude, yellow monoethylester of 'y-[3-(1-ethyl)-indolyl] y-keto-propylphosphonic acid whichmelted at 103 to 105 degrees centrigrade. Two recrystallizations fromchloroform-petroleum ether gave the purified monoethyl ester whichmelted at 118.5 to 119.5 degrees centigrade.

Ar'zalysis.--Calcd. for C H NO P: C, 58.25; H, 6.52; N, 4.53; P, 10.01;N. B. 309.29. Found: C, 58.32; H, 6.62; N, 4.75; P, 9.88; N. E. 310.0.

The monoethyl ester was dissolved in water containing sodium hydroxidein an amount which was equimolar with respect to the ester. The solutionwas evaporated under vacuum at about 25 degrees centrigrated to producemonosodium monoethyl 'y-[3-(l-ethyl)-indolyl-'y-keto-propylphosphonate.

EXAMPLE 3 Diethyl ester of 'y-(3-indolyl)-' -ket0-pr0pylphosphonic acidA. '2-DIMETHYLAMINOETHYL 3INDOLYL KETONE METHIODIDE A mixture of 15.9grams of 3-indolyl methyl ketone, (Saxton, J. Chem. Soc. 1952, 3592),8.15 grams of dimethylamine hydrochloride, 4.5 grams ofpara-formaldehyde and 150 milliliters of absolute ethanol was refluxedfor 24 hours. The clear brown solution was allowed to stand at 25degrees centigrade for 24 hours and was then evaporated under vacuum toa viscous oil. Water (200 milliliters) was added and the mixture wasfiltered. The aqueous filtrate was extracted twice with ether. The clearaqueous solution was then cooled with an ice bath and made alkaline witha cold solution of potassium hydroxide (ten grams) in 25 milliliters ofwater. The resulting mixture was extracted three times with chloroformand the combined chloroform extracts were washed twice with saturatedaqueous sodium chloride solution, and dried over anhydrous sodiumsulfate. The chloroform was re moved by evaporation to produce 13.]grams of 2-di methylaminoethyl 3-indolyl ketone free base.

Methyl iodide (1.42 grams; 0.01 mole) was added to a solution of 1.08grams of Z-dimethylaminoethyl 3-indolyl ketone free base in sixmilliliters of methanol cooled, with ice bath cooling. The mixture wasallowed to stand in the cold for four hours. The mixture was filteredand the precipitate washed with cold methanol to produce 1.53 grams ofZ-dimethylaminoethyl 3-indolyl ketone methiodide which melted at 205.5to 207.5 degrees centigrade.

Analysis.-Ca1cd. for C H IN O: C, 46.94; H, 5.35; N, 7.82; I, 35.43; C,47.03; H, 5.50; N, 7.58; I, 35.39.

B. DIETHYL ESTER OF 'y-(3-INDOLYL)-'y-KETO-PROPYL- PHOSPHONIC ACID Amixture of 21.4 grams (0.06 mole) of 2-dimethylaminoethyl 3-indolylketone methiodide and 100 grams (0.6 mole) of triethyl phosphite wasrefluxed gently for three hours (bath temperature 185 to 195 degreescentigrade). A crystalline solid collected in the upper part of theflask and in the mouth of the condenser, and a clear yellow solution wasobtained. The solution was allowed to cool to about 25 degreescentigrade, whereupon 100 milliliters of benzene was added and theresulting suspension was allowed to stand for about ten hours. Thesuspension was filtered to remove trimethylethylammonium iodide.

The filtrate was washed twice with cold water and once with saturatedaqueous sodium chloride solution. The washed solution was then driedover anhydrous magnesium sulfate and was evaporated'at reduced pressuredown to about 0.1 millimeter of mercury pressure, in order to remove theexcess triethyl phosphite. A quantitative yield 'of crude diethyl esterof 'y-(3-indolyl)-'y-keto-propylphos- EXAMPLE 4 Mixture of monoethylester of 'y-[3-(1-ethyD-ind0lylll- 'y-keto-propylphosphonic acid andmonoethyl ester of 'y-(3-ind0lyl) -keto-propylphosphonic acid A mixtureof 0.03 mole of the crude, 'oily diethyl ester of'y-(3-indolyl)-'y-keto-propylphosphonic acid and a solution'of 16.8grams of potassium hydroxide in milliliters of water was heated withstirring on the steam bath for seven hours, a clear yellow solutionbeing obtained after the first hour. The clear solution was then allowedto stand at about 25 degrees centigradefor about ten hours and was thencooled in ice and acidified with 29 milliliters of concentratedhydrochloric acid diluted with 25 milliliters of water. The resultingyellow oil was extracted three times with chloroform. The combinedchloroform extracts were washed successively with water and saturatedaqueous sodium chloride solution, and were then dried over anhydrousmagnesium sulfate. The solu' tion was then evaporated to dryness atabout 25 degrees centigrade at reduced pressure. There was thus obtained7.1grams of a yellow oil which upon several hours standing changed to anoily solid, consisting of 92 percent of the monoethyl ester of -y[3-(l-ethyD-indolyll-y-ketopropylphosphonic acid and eight percent of themonoethyl ester of 'y-(3-indolyl)--y-keto-propylphosphonic acid, asdetermined by quantitative infrared comparison with samples of the pureesters.

The oily solid was recrystallized from methanol-ether petroleum etherand then from ethyl acetate-ether. The resulting monoethyl ester of'y-IS-(I-ethyD-indOIyII-q' keto-propylphosphonic acid was identical tothe product of Example 2. I

EXAMPLE 5 Dimethyl ester of 7-[3-(I-ethyl)indolyl]-y-ket0-propylphosphonic acid A mixture of 7.45 grams of 2-dimethylarninoethyl3- (l-ethylindolyl) ketone methiodide and 24.8 grams of trimethylphosphite was refluxed for three hours. The bath temperature was 150 to172 degrees centrigrade. The resulting suspension was cooled, fiftymilliliters of benzene was added, and the suspension was filtered. Thefiltrate was washed successively with cold water and saturated aqueoussodium chloride solution. The washed solution was then dried oversodium'sulfate and was evaporated to dryness under vacuumto produce 5.04grams of yellow oil. The yellow oil was dissolved in milliliters ofether, the solution was filtered, and evaporated to cloudiness. Seedinginduced immedate crystallization of the dimethyl ester ofv-[3-(1-ethyl)-indolyl]- 'y-keto-propylphosphonic acid; the yield was3.9 grams and the melting point was 72 to 73.5 degrees Centigrade. Anadditional one gram was obtained as a second crop.

Analysis.-Calcd. for C I-I NO P: C, 58.25; H, 6.52; N, 4.53; P, 10.01.Found: C, 58.02; H, 6.54; N, 4.46; P, 10.16.

EXAMPLE 6 Diethyl ester of-[3-(1-methyl)-Indolyl]-'y-ketopropylphosphanic acid In the same manneras shown in Example 1, 2-dimethylaminocthyl 3 (1 methylindolyl) ketonehydrochloride was prepared using 1'methyl-3-acetylindole instead of1-ethyl-3-acetylindole, isolating the product by evaporating thereaction mixture, and recrystallizing the residue from methanol-ether.

A mixture of 1.7 grams of 2-dimethylaminoethyl 3-(1-methylindolyl)-ketone hydrochloride and 10.6 grams of triethyl phosphitewas heated at abathtemperature of aerasss 1'81! to, 195degreescentrigrade for 65 minutes. There suiting. solution was cooledand diluted with 150 milliliters of benzene. The benzene solution waswashed once with water, twice with saturated aqueous sodium chloridesolution, dried over anhydrous sodium sulfate, and evaporated to drynesson the stream bath at reduced pressure to produce the diethyl ester ofy-[3-(1-rnethyl)indolyllyrketo-propylphosphonic acid in substantiallyquantita tive yield.

EXAMPLE 7 Monoelhyl ester of 'y-[3-(1-merhyi) -indlyi]-y kct0-propylphosphonic acid 1 The above diethyl ester of'y-[3-(1-methyl)-indolylly-keto-propylphosphonic acid was heated on asteam bath with stirring for eight hours with a solution of 3.6 grams ofpotassium hydroxide in 21 milliliters of water. The resulting clear,brown solution was cooled and acidified with ten milliliters ofconcentrated hydrochloric acid, and this mixture was extracted threetimes with chloroform. The combined chloroform extracts were washedtwice with saturated aqueous sodium chloride solution, dried withanhydrous sodium sulfate, and evaporated to dryness at about. 25 degreescentigrade under reduced pressure. The residual oil was triturated withwarm ethyl acetate, to obtain the monoethyl ester of -[3-(1-metl1yl)-indolyl]-'y-keto-propylphosphonic acid as a yellow solid which had amelting point of 195 to 200 degrees centigrade.

ExAMPLn 8 Dimethyl ester of y-(3-ind0lyD-y-ket0- propylplzosphonic acidA mixture of 35.8 grams of Z-dimethylaminoethyl 3- indolyl ketonemethiodide and 124 grams of trimethyl phosphite was heated for three andone-half hours at a bath temperature of 153 to 163 degrees Centigrade.The reaction mixture was cooled, diluted with 100 milliliters ofbenzene, and allowed to stand for about ten hours. The precipitatedtetramethylammonium iodide was removed by filtration and the yellowfiltrate was evaporated to dryness under vacuum. The resulting oilyresidue was dissolved in chloroform; the solution was washed twice withwater, once with saturated aqueous sodium chloride solution, and driedover anhydrous sodium sulfate. The dried chloroform solution wasevaporated at about 25 degrees centigrade under vacuum, to give 21.6grams of the dimethyl ester of 'y-(3-indolyl)w-lteto-propylphosphonicacid as an oil. A sample of the oily dimethyl ester was crystallizedfrom methanol-ether-petroleum ether in the cold, and then recrystallizedsuccessively from benzene and from benzene-ether. The dimethyl esterthus purified melted between 123.5 and 125 degrees centigrade.

Analysis.-Calcd. for (F I-1 N0 1: C, 55.51; H, 5.74; N, 4.98. Found: C,55.64; H, 5.67; N, 4.75.

EXAMPLE 9 Mixture of monomethyl ester 0 'y-(3-irzd0Zyl)-y-kez0-propylphosphonic acid and monometlzyl ester of 'y-[3- (1 -methyl-ind0Iyl --,'keio-propyiphospizoiiic acid A mixture of 19.7 grams of thedimethyl ester of -(3- indolyl)-- -keto-propylphosphonic acid, 19.6grams of potassium hydroxide and 75 milliliters of water was heated onthe steam bath with stirring for four hours. The solution was filtered,cooled and acidified with 33 milliliters of concentrated hydrochloricacid. T he resulting precipitate was filtered, washed with water, anddried.to'give14.4 grams ofmonomethyl ester product, melting at 126degrees centigrade with efiervescence, andiconsistingof approximately 79percent of the monomethyl ester of ,-(3-indolyl)-'-leto-propylphosphonic acidand 21 percent of the monomethyl ester of-13-(1- methyl)-indolyl]-y-keto-propylphosphonic acid. This compositionwas. determined by esterifying themixed monomethyl ester product withdiazoiflethane, and ing out a quantitative infra'red assay on the"res'liltirig mixed dimethyl ester product.

EXAMPLE 1O Diisopropyl ester of -(3 -ind0lyl)w-keto-prapylphosphonicacid A mixture of 35.8 grams of Z-dimethylaminoethyI 3' indolyl lzetonemethiodide and 208 grams of triisopro'pyl phosphite was refluxed for 3.5hours. The resulting suspension was cooled, diluted with milliliters ofbenzene, allowed to stand for a few minutes, and filtered to removetrimethylisopropylammonium iodide.- After a few minutes a colorlessmaterial started to crystallize'in the filtrate. The crystals wererecovered by filtration; washed. successively with benzene and water,and dried to give 14.6 grams of the diisopropyl ester of *y-(3- indolyl)y-keto-propylphosphonic acid which melted between 128 and 129.5 degreescentigrade. The filtrate was evaporated to dryness under vacuumand'the'oily residue was dissolved in methylene chloride. The solutionwas washed with water, then with saturated aqueous sodium chloridesolution, and dried over anhydrous sodium sulfate. The solution wasevaporated to drynessat about 25 degrees eentigrade under vacuum to givean oily residue which crystallized on standing about ten hours. Thecrystalline material was triturated with ether to give an additional9.78 grams of the diisopropyl ester ofy-(S-indolyl)-y-ketopropylphosphonic acid, melting.

point 127 to 128 degrees centigrade. An analytical sample prepared byrecrystallization fronr benzenepetroleum ether had a melting point of129 to 130 degrees centigrade. I A Analysis.Calcdl for Ci H NO P: C,60.52; H, 7.17; N, 4.15. Found: C, 60.89; H, 7.40; N, 4.17.

EXAMPLE 11' Monoisopropyl ester of 'y-(3-indolyl)-'y'-keto-propylphosphonic acid A mixture of 13.6 grams ofthe'diisopropyl ester of y"- (B-indolyl)-- -keto-propylphosphonic acid,12.3 grams'of potassium hydroxide and 110 milliliters of water washeated on the steam bath with stirring for 22 hours; The mixture wascooled and extracted twice with ether; The aqueous alkaline solution wascooled and acidified with 21 milliliters of concentrated hydrochloricacid. The re sulting precipitate was recovered by filtration, washedwith water, and dried to give 11.1 grams of crude mono isopropyl esterof 'y- S-indolyl -y-lteto-propylphosphonic acid which melted between and157 degrees centigrade with eltervescence. One gram of monoisopropylester of 'y-(3-indolyl)--y-keto-propylphosphonic acid was dissolved in950 milliliters of acetone and the solution was evaporated to about 100milliliters whereupon crystallization began. Colorless plates ofmonoisopropyl ester of 'y-(3-indolyl)-'y-l eto-propylphosphonic acidwereob tained which melted between 173 and 174.5 degrees centi grade.

Analysis-Calcd. for C H N0 P: C, 56.95; H, 6.14; N, 4.74. Found: C,57.19; H, 6.29; N, 4.73.

The monoisopropyl ester was dissolved in an excess of dilute ammoniumhydroxide. The solution was evapo rated under vacuum at about 25 degreescentigrade to'ob tain monoammonium monois'opropyl -(3-indolyl)-'y=keto-propylphosphon'ate.

ExAMrLu 12 Dimetlzyl ester of -[3-(5-berizyloxy)indolyil-y-ketmpropylphospltonic acid A" mixture of 25.16 & grams of Z-dimethylaminOetliyY 3-(5-benzyloxy)-indolyl ket'one hydrochloride and86:8 grams of trimethyl phosphite was heated for-three hours at a bathtemperature of 155 to 158 degrees'centigrad. The excessof trimethy-lphosphite- 'was distilled under vacuum. The residue was cooled in iceanddiluted with '100 milliliters of benzene and 100 milliliters of coldwater. A thick colorless precipitate was formed, 25 milliliters ofmethanol was added, and the mixture was filtered to yield 16.23 grams ofcrude, solid product. The product was recrystallized from eightymilliliters of methanol and 100 milliliters of ether to yield 7.59 gramsof dimethyl ester of7-[3-(S-benzyloxy)-indolyl]--,'-ketopropylphosphonic acid which meltedbetween 146 and 146.5 degrees centigrade. A secondcrop which amounted.to 4.56 grams of product was also obtained. The melting point of ananalytical sample obtained by recrystallization from methanol-ether was147.5 to 148 degrees Centigrade.

Analysis.-Calcd. for C H NO P: C, 62.01; H, 5.72; N, 3.61; P, 7.99.Found: C, 61.75; H, 5.33; N, 3.81;

EXAMPLE 13 Monomethyl ester of 'y-[3-(5-benzyl0xy),-ind0lyl]-'y-keto-propylphosphonic acid A mixture of 13.22 grams of dimethyl esterof -[3-(5- benzyloxy)-indolyl]-'y-keto-propylphosphonic acid, 9.1 gramsof potassium hydroxide and 35 milliliters of water i was heated on asteam bath with stirring for eight hours. The mixture was cooled andacidified with 26 milliliters of concentrated hydrochloric acid. An oilysolid was produced, 800 milliliters of chloroform was added, and thesolid material was recovered by filtration. The solid was washed withchloroform, then with water, and dried, to yield 11.21 grams of themonomethyl ester of 'y-[3-(5-benzyloxy)-indolyl]-'y-keto-propylphosphonic acid which melted between191 and 192.5 degrees centigrade. The compound after tworecrystallizations from dimethyl- I formamide-ether melted between 196.5and 197.5 degrees centigrade.

EXAMPLE 14 Diethyl ester of'y-[3-(5-benzyloxy)-indolyl]-'y-ketopropylphosphonic acid A mixture ofthirty grams of Z-dimethylaminoethyl 3- (5-benzyloxy)-indolyl ketonehydrochloride and 140 grams of triethyl phosphite was heated (bathtemperature 180 to 190 degrees centigrade) for 2.75 hours. The solutionwas cooled, diluted with 100 milliliters of benzene,

and allowed to stand for ten hours. The mixture was filtered and thesolid thus recovered was washed with benzene and dried, to yield 22.5grams of diethyl ester of'y-[3-(5-benzyloxy)-indolyl]w-keto-propylphosphonic acid having amelting point between 166.5 and 167.5 degrees centigrade. An analyticalsample prepared by recrystallization from ethanol melted between 169.5and 170 degrees centigrade.

Analysi.r.--Calcd. for C H NO P: C, 63.60; H, 6.31; N, 3.37; P, 7.45.Found: C, 63.91; H, 6.63; N, 3.64; P, 6.98.

' In the same manner other dialkyl esters of 7-[3-(5- henzloxy) indolyl]-y keto propylphosphonic acid "are prepared by reacting aZ-sec-aminoethyl 3-indolyl ketone quaternary ammonium saltor acidaddition salt with a primary or secondary trialkyl phosphite, e. g.,diiso propyl ester of'y-[3-(5-benzyloxy)-indolyl]-'y-keto-propylphosphonic acid is preparedby reacting triisopropyl phosphite with 2-dimethylaminoethyl3-(5-benzyloxy)-indolyl ketone hydrochloride; dibutyl ester of'y-[3-(5-benzyloxy)-indolyl] -'y-keto-propylphosphonic acid is preparedby reacting tributyl phosphite with Z-dimethylaminoethyl 3-(5-benzyloxy)-indolyl ketone hydrochloride; dipropyl ester of'y-[3-(5-benzyloxy)-indolyl]*y-keto-propylphosphonic acid is prepared byreacting tripropyl phosphite with 2-dimethylaminoethy13-(5-benzyloxy)-indolyl ,ketone sulfate; dimethyl ester of'y-[3-methyl-5-benzyloxy)- indolyl]-'y-keto-propylphosphonic acid isprepared by reacting trimethyl phosphite with Z-dimethylaminoethyl 3-(l-methyl-5-benzyloxy)-indolyl ketone hydrochloride; di-

'ethyl ester of y-i3-( l-ethyl-S benzyloxy) -indolyl] 5.1km

propylphosphonic acid is prepared by reacting trietliyl phosphite withZ-dimethylaminoethyl 3-(1-ethyl-5-henzyloxy)-indolyl ketone sulfate;dipropyl ester of 'y-[3-(1- butyl 5 benzyloxy) indolyl] 'y ketopropylphosphonic acid is prepared by reacting tripropyl phosphite withZ-dimethylaminoethyl 3-( l-butyl-S-benzyloxy) -indolyl ketonehydrochloride; and dibutyl ester of v-[3-(1-hexyl-5-benzyloxy)-indolyl]w-keto-propylphosphonic acid is prepared by reactingtributyl phosphite with Z-dimethylamino-ethyl3-(l-hexyl-S-benzyloxy)-indolyl ketone etho bromide.

EXAMPLE 15 Monoethyl ester of-[3-(5-benzyl0xy)indolyl]-q-ketapropylphosphonic acid A mixture offifteen grams of diethyl ester of 743-6-benzyloxy)-indolyl]--y-keto-propylphosphonic acid, 10.1 grams ofpotassium hydroxide, and 87 milliliters of water was heated on the steambath with stirring for eight hours. The mixture was cooled with ice,acidified with twenty milliliters of concentrated hydrochloric acid, andfiltered. The recovered solid was washed with water and dried to yieldfourteen grams of monoethyl ester of 7-[3- (5 benzyloxy) indolyl] v ketopropylphosphonic acid which melted at 179 degrees centigrade withdietvescence. This product after recrystallization from ethan01 meltedbetween 173.5 and degrees 'centigrade. I

Analysis.Calcd. for C H NO P: C, 62.01; H, 5.72; N, 3.62. Found: C,61.53; H, 5.64; N, 3.72. I

In the same manner other monoalkyl esters of 'y-[3-(5- benzyloxy)indolyl] 'y keto propylphosphonic acid are prepared by hydrolyzing thecorresponding dialkyl ester of 3- S-benzyloxy -indolyl]w-keto-propylphosphonic acid, e. g., the monoisopropyl esterof-'y-[3-(5- benzyloxy)-indolyl]-'y-keto-propylphosphonic acid, the

'monobutyl ester of v-[3-(S-benzyloxy) indolyll y-keto propylphosphonicacid, monopropyl ester of'y-[3-(5-b'enzyloxy)-indolyl]q-keto-propflphosphonic acid, mono methylester of -y-[3-( l-methyl-S-benzyloxy)-indolyl1 -'yketo-propylphosphonicacid, monopropyl ester of 7-[3-(1- butyl 5 benzyloxy) indolyl] 'y ketopropylphosphonic acid, monobutyl ester of -[3-(l-hexyl-5-benzyLoxy)-indolyl]-' -keto-propylphosphonic acid, are prepar by hydrolyzingthe corresponding dialkyl ester.

EXAMPLE 16 Monoethyl ester of 'y-[3-(I-ethyl-S-benzyloxy)-ind0lyl]-'y-keto-propylphosphoriic acid The monoethyl ester of -[3 (5-benzyloxy)-indolyl]- -y-keto-propylphosphonic acid (3.87 grams; 0.01 mole) was:dissolved in 47 milliliters of ten percent aqueous sodium hydroxidesolution and 6.5 milliliters (0.05 mole) of diethyl sulfate was addeddropwise while the reaction mixture was stirred and heated onthe steambath. When the exothermic reaction-had subsided, 37 milliliters of tenper.

cent aqueous sodium hydroxide solution was added, fol

lowed by 6.5 milliliters of diethyl sulfate, and the reaction mixturewas stirred and heated for 1.5 hours. The clear yellow alkaline solutionwas cooled and acidified with twenty milliliters of concentratedhydrochloride acid. The resulting oily material was removed from themixture by three extractions with chloroform. The combined chloro.

. EXAMPLE 17 r v Dimethyl ester of'y-[3-(5-hydroxy)indolyl]-y-ketdpropylphosphonic acid I,

A suspension of 1.94 grams of dimethyl ester of 7423- (5 benzyloxy)indolyl] --'y keto propylphosphonie esta es;

1! Mid in 100 milliliters of 95 percent ethanol was hydro.- genated at48 pounds of hydrogen pressure in the presenceof 0.2 gram ofpalladinm-on-carbon catalyst. After five hours 100 milliliters ofethanol was added and the suspension was filtered. The filtratewas-evaporated to about five milliliters whereupon crystallizationoccurred to give 0.53 gram of the dimethyl ester of'y-[3-(5-hydroxy)-indolyl] -ket-propylph0sphonic acid which melted at223 degrees centigrade with decomposition.

Analysis.Calcd. for C H NO P: C, 52.53; H, 5.43; N, 4.71. Found: C,52.91; H, 5.56; N, 4.99.

In the same manner the following esters of -[3-(5-hydroxy)-keto-propylphosphonic acid are prepared by subjecting the correspondingbenzyloxy derivative to hydrogenolysis in the presence of a palladiumcatalyst: diethyl ester of 'y [3 (5 hydroxy) indolyl] 'y ketopropylphosphonic acid, diisopropyl ester of 'y-[3-(5-hydroxy)- indolyl]"late-propylphosphonic acid, dibutyl ester of 'y [3 (5 hydroxy) indolyl]'y keto propylphosphonic acid, dipropyl ester of-[3-(5-hydroxy)-indolyll- 'y-keto-propylphosphonic acid, dimethyl esterof -[3-(1- methyl-S-hydroxy)-indolyl]-- -keto-proylphosphonic acid,diethyl ester of v-[3-(l-ethyl-S-hydroxy)indolyl]-rhetopropylphosphonicacid, dipropyl ester of 'y-[3-(1-butyl-5-hydroxy)-indolyl]w-keto-propylphosphonic acid, dibutyl ester of *y- 31-hexyl-5-hydroxy)-indolyl]-'y-keto-propylphosphonic acid, dipropylester of 'y-[3-(l-amyl-5-hydroxy)-indolyl]-'y-keto-propylphosphonicaicd, monoethyl ester of '7, [3 (5 hydroxy) indolyl] 'yketopropylphosphonic acid, monomethyl ester of -y-[3-(5-hy-.droxyyindolyl]-- -keto-propylphosphonic acid, monoethyl ester-of v [3(1 propyl 5 hydroxy) indolyl] 'yheto' propylphosphonic acid,monoisopropyl ester of v [3 (5 hydroxy) indolyl] v keto propylphosphonicacid, monobutyl ester of 'y-[3-(5-hydroXy)-indolyl] 'y ketopropylphosphonic acid, monopropyl ester of 'y [3 5 hydroXy) indolyl] 'yketo propyl: phosphonic acid, monomethyl ester of 'y-[3-(l-methyl- 5hydroxy) indolyl] 'y -propylphosphonic acid, monoethyl ester of 'y [3 (1ethyl 5 hydroxy) indolyl] hoto-propylphosphonic acid, monopropyl esterof v [3 (1 butyl 5 hydroxy) indolyl 'y ketopropylphosphonic acid,monobutyl ester of 7-[3-(1-116XY1- S hydroxy) indolyl] 'y ketopropylphosphonic acid, monopropyl ester of 'y-[3-(l-amyl-5-hydroxy)-'keto-propylphosphonic acid.

EXAMPLE 18 Dimethyl ester propylphosphonic acid The monomethyl ester of'y-[3-(5-benzyloxy)-indoly1]- y-ketopropylphosphonic acid was treatedwith an excess of ethereal diazomethane solution to produce the dimethylester or v-[3-(5-benzloxy)-indolyl]whom-propylphosphonic acid whichmelted between 146 and 147 degrees centigrade. This product was shown tobe identical with the product of Example 12, by mixed melting point andby infrared comparison.

EXAMPLE 19 .dissolved in ethanol, and to this solution was added an etheso ut n o azce ne, th qu n ty o d a oe ene being .eguimolar with respectto the y-'(3.-indolyl).- y.-keto- Isopropyl butyl *y-(S-indolyl)w-keto-propylphosphonate An other solution of diazobutane (0.01 mole)was added to an ethanol solution of themonoisopropyl ester of-(3-indolyl)-v-keto-propylphosphonic acid (0.01 mole). The reactionmixture was allowed to stand at about 25 degrees centigrade for fourhours, and was then evaporated to dryness at about 25 degrees centigradeand reduced pressure, to obtain isopropyl butyl -(3-indolyl)--keto-propylphosphonate.

In the same manner other mixed esters are prepared by reacting aselected monoalkyl ester with a diazoalkane, e. g., ethyl propyl'y'-(3-indolyl)- -keto-propylphosphonate is prepared by reacting themonoethyl ester of -(3-indolyl)-y-keto-propylphosphonic acid withdiazopropane; methyl butyl -(3-indolyl)r-y-ketopropylphosphonate isprepared by reacting the monomethyl ester ofry-(3-indolyl)--y-keto-propylphosphonic acid with diazobutane; methylbutyl 'y-[3-(5-benzyloxy)indolyl]-y-keto-propylphosphonate is preparedby reacting the monomethyl ester of-[3-(5-benzy1oxy)-indolyl]w-keto-propylphosphonic acid with diazobutane;methyl ethyl 'y-[3-(1-ethyl)- indolyl]-'y-keto-propylphosphonate isprepared by reacting the monoethyl ester of -[3- (l-ethyl)-indolyl]-'-ketopropylphosphonic acid with diazomethane; and ethyl propyl 'y- [3-(1-ethyl-5-benzyloxy) -indolyl] -'y-k eto-proylphosphonate is prepared byreacting the monoethyl ester of 'y [3-(l-ethyl-S-benzyloxy)-indolyl]-'y-keto-propylphosphonic acid with diazopropane.

It is to be understood that the invention is not to be limited to theexact compounds shown and described, as obvious modifications andequivalents will be apparent to one skilled in the art, and theinvention is therefore to be limited only by the scope of the appendedclaims.

I claim:

1. A compound represented by the following formula:

ii 3/ C CHRCHIP i w CHaCHaP wherein R; is a lower-alkyl radicalcontaining from one to six carbon atoms, inclusive, and R and Rare-primary lower-alkyl radicals containing fromone to four carbon aoms, inclusi 0 l Benzyloxy iJCHrCHgP N in wherein R is selected from thegroup consisting of hydrogen and a lower-alkyl radical containing fromone to six carbon atoms, inclusive, R is selected from the groupconsisting of a primary and a secondary lower-alkyl radical containingfrom one to four carbon atoms, inclusive, and R is selected from thegroup consisting of hydrogen, an alkali-metal, and a primary and asecondary lower-alkyl radical containing from one to four carbon atoms,inclusive.

5. Dimethyl ester of -[3-(l-ethyl)-indolyl]- -ketopropylphosphonic acid.

6. Dimethyl ester of 'y-[3-(5-hydroxy)-indolyl]yketo-propylphosphonicacid.

7. Monoisopropyl ester of 'y-(3-indolyl) y-keto-propylphosphonic acid.

, v 14 8. Monoethyl ester of-[3-(l-ethyl)-indolyl]-'y-ketopropylphosphonic acid.

9. Diisopropyl ester of -(3-indolyl)-'y-keto-propylphosphonic acid.

10. A compound represented by the following formula:

0 0 CR4 CHBOHH E wherein R is a lower-alkyl radical containing from oneto six carbon atoms, inclusive, and R and R are secondary lower-alkylradicals containing from one to four carbon atoms, inclusive.

11. A compound represented by the following formula:

0 OH CHnCHzii OR! N 1'11 wherein R is a lower-alkyl radical containingfrom one to six carbon atoms, inclusive, and R is a secondarylower-alkyl radical containing from one to four carbon atoms, inclusive.

References Cited in the file of this patent UNITED STATES PATENTS2,849,454 Smuszkovicz Aug. 26, 1958 UNITED STATES PATENT OFFICECertificate of Correction Patent No. 2,877,234 March 10, 1959 JacobSzmuszkovicz It is hereby certified that error appears in the abovenumbered patent requiring correction and that the said Letters Patentshould read as corrected below.

Column 9, line 72, Example 14, for y-[3-methylread y-[3-(1-methyl--;column 11, line 39, Example 17, for -prop lphosphonic read-keto-propylphosphonic-; column 11, line 61, Example 19, in the headingthereto, for ether read ester.

Signed and sealed this 28th day of July 1959.

[SEAL] KARL H. AXLINE, ROBERT C. WATSON, Attesting Ofiiaer. Commissionerof Patents.

1. A COMPOUND REPRESENTED BY THE FOLLOWING FORMULA: